Solutions of lactic acid salts of piperazinylquinolone- and piperazinyl-azaquinolone-carboxylic acids

ABSTRACT

The invention relates to solutions of piperazinylquinolone- and piperazinyl-azaquinolone-carboxylic acids, and in particular both ready-to-use injection and/or infusion solutions and dosage forms which can be converted into such injection and/or infusion solutions before use. The solutions according to the invention are characterized in that, besides the lactic acid salts of the active substance and, if appropriate, customary auxiliaries, they additionally contain at least one acid which does not lead to precipitates, in particular lactic acid.

This is a division of application Ser. No. 862,343, filed 5-12-86, nowpending, which is a division of Ser. No. 644,834, filed 8-27-84, nowU.S. Pat. No. 4,705,789.

The invention relates to solutions of piperazinylquinolone- andpiperazinyl-azaquinolone-carboxylic acids, and in particular bothready-to-use injection and/or infusion solutions and dosage forms whichcan be converted into such injection and/or infusion solutions beforeuse.

The solutions according to the invention are characterised in that,besides the lactic acid salts of the active substance and, ifappropriate, customary auxiliaries, they additionally contain at leastone acid which does not lead to precipitates, in particular lactic acid.

Possible active substances are at least one of the compounds of theformulae I or II ##STR1## in which X denotes N, C--H or C--F,

Z denotes O or CH₂,

R₁ denotes hydrogen methyl, ethyl or β-hydroxyethyl,

R₂ denotes cyclopropyl or ethyl and

R₃ denotes hydrogen, methyl or ethyl.

Compounds which may be mentioned in particular are:1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylicacid (compound A);1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylicacid (compound B);9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylicacid (compound C);1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylicacid (compound D); and1,cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-ethyl-1-piperazinyl)-quinoline-3-carboxylicacid (Compound E).

These substances are known to have powerful antibacterial action and aretherefore suitable as medicaments for combating bacterial infections inwarm-blooded animals.

The compounds of the formula I are known from: J. Med. Chem. 23 1958(1980); DE-OS (German Published Specification) No. 3,142,854; DE-OS(German Published Specification) No. 3,033,157; and EP-OS (EuropeanPublished Specification) No. 0,067,666.

The compounds of the formula II are known from: EP OS (EuropeanPublished Specification) No. 0,047,005; DE-OS No. (German PublishedSpecification) 3,037,103; and DE-OS No. (German Published Specification)2,914,258.

Suitable customary auxiliaries for the solutions according to theinvention are non-toxic, pharmaceutical carrier substances. These are,for example, thickeners, absorption accelerators, absorption inhibitors,crystallisation retarders, complexing agents, antioxidants, isotonicityagents or euhydrating agents. They can be solid, semisolid or liquid inconsistency.

Examples of possible acids which do not lead to precipitates aremethanesulphonic acid, propionic acid, succinic acid, hydrochloric acidand, in particular, lactic acid.

For various reasons, acid addition salts or alkali metal salts of activecompounds are frequently used in pharmacy. Addition salts of the activesubstances can be prepared from several inorganic and organic acids,such as, for example, sulphuric acid, nitric acid, hydrochloric acid,citric acid, acetic acid, malic acid, succinic acid, tartaric acid,fumaric acid and methanesulphonic acid.

However, many such salts are unsuitable or very poorly suitable for thepreparation of infusion and/or injection solutions, because, forexample, the pH and/or the solubility and/or the shelf life, especiallyin respect of deposits, of the ready-to-use infusion and/or injectionsolution does not fulfil the pharmaceutical requirements to be imposedon such solutions.

It has now been found that the solutions can be stored if, besides thelactic acid salt of at least one of the active substances and, ifappropriate, customary auxiliaries, they additionally contain at leastone acid which does not lead to precipitates, in particular lactic acid.

The presence of such acids, in particular lactic acid, or, depending onthe pH, a mixture of acid(s) and anion(s) thereof, is essential for thestability of the solution to be administered, in particular in respectof deposits.

Depending on the primary means of packaging used, the concentration ofthe active substance in the solution, the pH of the solution and theshelf-life requirements imposed, the content of excess lactic acid ofthe solutions according to the invention can be 0.01 to 90%. The lacticacid content of the solution to be administered can be 0.01 to 25%preferably 0.025 to 1.4%.

These quantity data relate to the total amount of excess acid, that isto say non-dissociated and dissociated acid.

Where these acids required for the stability are referred to below, inparticular lactic acid, the total amount of excess acid is meant that isto say non-diisociated and dissociated acid.

If other acids which do not lead to precipitates are used, such as, forexample, methanesulphonic acid, propionic acid, hydrochloric acid orsuccinic acid, the content of excess acid can be 0.05 to 4%, preferablybetween 0.3 and 2%, depending on the concentration of the activesubstance, the shelf-life requirements imposed and the pH of theready-to-use solutions according to the invention.

The pH of the ready-to-use solutions according to the invention can bebetween 2.5 and 7, preferably between 3.5 and 4.5.

It was very surprising to discover that by addition of at least one acidwhich does not lead to precipitates, in particular lactic acid, inamounts such as those given above, it was also possible to stabiliseinfusion and/or injection solutions of the lactic acid salt of compoundB, D and E, whilst the 1:1 stoichiometric salts of these compoundstended to give deposits. This also applies to the formulations,according to the invention, of compound C.

It has furthermore been found that there are several possible processesfor the preparation of the solutions according to the invention.

The lactic acid salt of the active substance or a hydrate thereof can beused as the starting substance for the preparation of the solution ofthe active substance. In this case, it is possible to incorporate therequired addition, or some of this addition, of at least one acid whichdoes not lead to precipitates, in particular lactic acid, into thelactic acid salt, for example by freeze-drying.

However, the lactic acid salts can also be prepared directly in thesolution, and in particular by addition of the amounts of lactic acidrequired for salt formation.

It is in this way possible to prepare both ready-to-use solutions of theactive substance, filled in suitable containers, for example in ampoulesor injection or infusion bottles, as well as precursors, for exampleconcentrates or ampoules, suitable for the preparation of suchsolutions.

The solutions according to the invention, like the compounds of theformulae I and II on which they are based, are to be used as medicamentsfor combating bacterial infections. Possible uses are as injections andinfusions. The dosages correspond to those of the known compounds A, B,C, D and E. Unless otherwise specified, all parts and/or percentages asused herein are parts or percentages by weight per unit volume.

FORMULATIONS

The solutions according to the invention are prepared by dissolving theactive substance or the lactic acid salt thereof and, if appropriate,customary auxiliaries, in a solution of lactic acid or a mixture oflactic acid and, for example, sodium lactate, if necessary with slightwarming.

If appropriate, water or a mixture of water and sodium hydroxidesolution is also added to adjust the desired concentration of the activesubstance and/or the pH of the solution.

EXAMPLE 1

    ______________________________________                                        1-Cyclopropyl-6-fluoro-1,4-dihydro-4-                                                                  150    g                                             oxo-7-(1-piperazinyl)-quinolone-3-                                            carboxylic acid (compound A)                                                  Lactic acid (90% by weight)                                                                           262     g                                             2 M sodium hydroxide solution                                                                         266     g                                             Water                   to 15.0 liters                                        ______________________________________                                    

EXAMPLE 2

    ______________________________________                                        Monolactate of compound A                                                                              1.27   g                                             Lactic acid (90% by weight)                                                                           1.45    g                                             2 M sodium hydroxide solution                                                                         1.80    g                                             Mannitol                1.37    g                                             Water                   to 100.0                                                                              ml                                            ______________________________________                                    

EXAMPLE 3

    ______________________________________                                        Compound A              10.00   g                                             Lactic acid (90% by weight)                                                                          4.85     g                                             Water                  to 1000.0                                                                              ml                                            ______________________________________                                    

EXAMPLE 4

    ______________________________________                                        1-Ethyl-6-fluoro-1,4-dihydro-4-                                                                       1.00    g                                             oxo-7-(1-piperazinyl)-quinolone-                                              3-carboxylic acid (compound B)                                                Lactic acid (90% by weight)                                                                          0.50     g                                             Glucose                3.85     g                                             Water                  to 100.00                                                                              ml                                            ______________________________________                                    

EXAMPLE 5

    ______________________________________                                        9-Fluoro-3-methyl-10-(4-methyl-1-                                                                      5.00    g                                            piperazinyl)-7-oxo-2,3-dihydro-7H--                                           pyrido-[1,2,3-de]-4-benzoxazine-6-                                            carboxylic acid (compound C)                                                  Lactic acid (90% by weight)                                                                           2.20     g                                            Water                   to 100.00                                                                              ml                                           ______________________________________                                    

EXAMPLE 6

    ______________________________________                                        Dihydrate of the monolactate of                                                                       69.0    g                                             compound A                                                                    Lactic acid (90% by weight)                                                                          24.2     g                                             Water                  to 1000.0                                                                              ml                                            ______________________________________                                    

EXAMPLE 7

    ______________________________________                                        Compound A              300.0   g                                             Lactic acid (90% by weight)                                                                          177.3    g                                             Water                  to 6000.0                                                                              ml                                            ______________________________________                                    

EXAMPLE 8

    ______________________________________                                        Compound A              200.0   g                                             Lactic acid (90% by weight)                                                                          75.0     g                                             Water                  to 2000.0                                                                              ml                                            ______________________________________                                    

EXAMPLE 9

    ______________________________________                                        Monolactate of compound B                                                                             128.2   g                                             Lactic acid (90% by weight)                                                                          50.0     g                                             Water                  to 1000.0                                                                              ml                                            ______________________________________                                    

EXAMPLE 10

    ______________________________________                                        Compound C              100.0   g                                             Lactic acid (90% by weight)                                                                          44.4     g                                             Water                  to 1000.0                                                                              ml                                            ______________________________________                                    

EXAMPLE 11

    ______________________________________                                        Compound A              30.0    g                                             Lactic acid (90% by weight)                                                                          to 100.0 g                                             ______________________________________                                    

EXAMPLE 12

    ______________________________________                                        Compound A             1.00     g                                             Lactic acid (90% by weight)                                                                          0.30     g                                             Succinic acid          0.71     g                                             Water                  to 100.00                                                                              ml                                            Adjusted to pH 3.6 with 2 M                                                   sodium hydroxide solution.                                                    ______________________________________                                    

EXAMPLE 13

    ______________________________________                                        Monolactate of compound A                                                                            1.27     g                                             Methanesulphonic acid  0.60     g                                             Water                  to 100.00                                                                              ml                                            Adjusted to pH 3.9 with 2 M                                                   sodium hydroxide solution.                                                    ______________________________________                                    

EXAMPLE 14

    ______________________________________                                        Monolactate of compound A                                                                            1.27     g                                             Lactic acid (90% by weight)                                                                          0.56     g                                             Methanesulphonic acid  1.45     g                                             Water                  to 100.00                                                                              ml                                            Adjusted to pH 3.7 with 2 M                                                   sodium hydroxide solution.                                                    ______________________________________                                    

EXAMPLE 15

    ______________________________________                                        Compound A             1.00     g                                             Lactic acid (90% by weight)                                                                          0.86     g                                             Propionic acid         1.12     g                                             Water                  to 100.00                                                                              ml                                            Adjusted to pH 3.8 with 2 M                                                   sodium hydroxide solution.                                                    ______________________________________                                    

EXAMPLE 16

    ______________________________________                                        Compound B             1.00     g                                             Lactic acid (90% by weight)                                                                          0.87     g                                             Propionic acid         0.46     g                                             Water                  to 100.00                                                                              ml                                            ______________________________________                                    

EXAMPLE 17

    ______________________________________                                        Monolactate of compound B                                                                        1.28         g                                             Lactic acid (90% by weight)                                                                      1.11         g                                             Succinic acid      1.85         g                                             Water              to 100.00    ml                                            ______________________________________                                         Adjusted to pH 3.7 with 2 M sodium hydroxide solution.                   

EXAMPLE 18

    ______________________________________                                        Compound B         1.00         g                                             Lactic acid (90% by weight)                                                                      0.42         g                                             Methanesulphonic acid                                                                            1.50         g                                             Water              to 100.00    ml                                            ______________________________________                                         Adjusted to pH 3.8 with 2 M sodium hydroxide solution.                   

EXAMPLE 19

    ______________________________________                                        Compound C         1.00         g                                             Lactic acid (90% by weight)                                                                      0.39         g                                             Methanesulphonic acid                                                                            0.53         g                                             Water              to 100.00    ml                                            ______________________________________                                         Adjusted to pH 3.9 with 2 M sodium hydroxide solution.                   

EXAMPLE 20

    ______________________________________                                        Monolactate of compound C                                                                        1.25         g                                             Lactic acid (90% by weight)                                                                      0.56         g                                             Propionic acid     1.03         g                                             Water              to 100.00    ml                                            ______________________________________                                    

EXAMPLE 21

    ______________________________________                                        Compound C         1.00         g                                             Lactic acid (90% by weight)                                                                      1.39         g                                             Succinic acid      0.64         g                                             Water              to 100.00    ml                                            ______________________________________                                         Adjusted to pH 3.7 with 2 M sodium hydroxide solution.                   

EXAMPLE 22

    ______________________________________                                        Compound A         1.00         g                                             Lactic acid (90% by weight)                                                                      0.33         g                                             1 M hydrochloric acid                                                                            1.20         g                                             Water              to 100.00    ml                                            ______________________________________                                    

EXAMPLE 23

    ______________________________________                                        Compound A         1.00         g                                             Lactic acid (90% by weight)                                                                      0.41         g                                             Water              to 100.00    ml                                            ______________________________________                                         Adjusted to pH 4.0 with 1 M hydrochloric acid.                           

EXAMPLE 24

    ______________________________________                                        Compound A         20.00        g                                             Lactic acid (90% by weight)                                                                      8.26         g                                             Water              to 100.00    ml                                            ______________________________________                                         Adjusted to pH 3.6 with 1 M hydrochloric acid.                           

EXAMPLE 25

    ______________________________________                                        Compound E         1.00         g                                             Lactic acid (90% by weight)                                                                      0.33         g                                             Water              to 100.00    ml                                            ______________________________________                                    

EXAMPLE 26

    ______________________________________                                        Compound E         1.00         g                                             Lactic acid (90% by weight)                                                                      0.44         g                                             Benzylalcohol      1.00         g                                             Water              to 100.00    m.                                            ______________________________________                                    

EXAMPLE 27

    ______________________________________                                        Compound E         1.00         g                                             Lactic acid (90% by weight)                                                                      0.33         g                                             1 M hydrochloric acid                                                                            0.66         g                                             Water              to 100.00    ml                                            ______________________________________                                    

EXAMPLE 28

    ______________________________________                                        Compound E         2.50         g                                             Lactic acid (90% by weight)                                                                      0.83         g                                             1 M hydrochloric acid                                                                            1.65         g                                             Water              to 100.00    ml                                            ______________________________________                                    

EXAMPLE 29

    ______________________________________                                        Compound E         10.00        g                                             Lactic acid (90 by weight)                                                                       8.33         g                                             Hydrochloric acid (25%)                                                                          1.30         g                                             Water              to 100.00    ml                                            ______________________________________                                    

EXAMPLE 30

    ______________________________________                                        Compound E         5.00         g                                             Lactic acid (90% by weight)                                                                      2.22         g                                             Sodiummetabisulfite                                                                              0.20         g                                             Water              to 100.00    ml                                            ______________________________________                                    

What is claimed is:
 1. An aqueous storage stable solution which can beconverted into an injection or diffusion solution consisting essentiallyof (a) a lactic acid salt of a piperazinylquinolone- orpiperazinyl-azaquinolone-carboxylic acid of the formula ##STR2## inwhich X denotes N, C--H or C--F,R₁ denotes hydrogen, methyl, ethyl orβ-hydroxyethyl, R₂ denotes cyclopropyl or ethyl and R₃ denotes hydrogen,methyl or ethyl, and (b) and excess acid selected from the groupconsisting of methanesulphonic acid, propionic acid, succinic acid andhydrochloric acid, the excess acid being present in an amount which doesnot lead to precipitates and constituting about 0.01 to 90% based on thesolution.
 2. A solution according to claim 1, which contains the lactateof1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylicacid.
 3. A solution according to claim 1, which contains the lactate of1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylicacid.
 4. A solution according to claim 1, which contains the lactate of1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthyridine-3-carboxylicacid.
 5. A solution according to claim 1 in which the content of excessacid is 0.01 to 25%.
 6. A solution according to claim 1, in which thecontent of excess acid is 0.025 to 1.4%.